Inflammation is the body's defense reaction to injuries such as those caused by mechanical damage, infection or antigenic stimulation. An inflammatory reaction may be expressed pathologically when inflammation is induced by an inappropriate stimulus such as an autoantigen, is expressed in an exaggerated manner or persists well after the removal of the injurious agents.
While the etiology of inflammation is poorly understood, considerable information has recently been gained regarding the molecular aspects of inflammation. This research has led to identification of certain cytokines which are believed to figure prominently in the mediation of inflammation. Cytokines are extracellular proteins that modify the behavior of cells, particularly those cells that are in the immediate area of cytokine synthesis and release. One of the most potent inflammatory cytokines yet discovered and a cytokine which is thought to be a key mediator in many diseases and medical conditions is interleukin-1 (IL-1). IL-1, which is manufactured (though not exclusively) by cells of the macrophage/monocyte lineage, may be produced in two forms: IL-1 alpha (IL-1.alpha.) and IL-1 beta (IL-1.beta.).
A disease or medical condition is considered to be an "interleukin-1 mediated disease" if the spontaneous or experimental disease or medical condition is associated with elevated levels of IL-1 in bodily fluids or tissue or if cells or tissues taken from the body produce elevated levels of IL-1 in culture. In many cases, such interleukin-1 mediated diseases are also recognized by the following additional two conditions: (1) pathological findings associated with the disease or medical condition can be mimicked experimentally in animals by the administration of IL-1; and (2) the pathology induced in experimental animal models of the disease or medical condition can be inhibited or abolished by treatment with agents which inhibit the action of IL-1. In most interleukin-1 mediated diseases at least two of the three conditions are met, and in many interleukin-1 mediated diseases all three conditions are met. A non-exclusive list of acute and chronic interleukin-1 (IL-1)-mediated inflammatory diseases includes but is not limited to the following: acute pancreatitis; ALS; Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes); glomerulonephritis; graft versus host rejection; hemohorragic shock; hyperalgesia, inflammatory bowel disease; inflammatory conditions of a joint, including osteoarthritis, psoriatic arthritis and rheumatoid arthritis; ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); lung diseases (e.g., ARDS); multiple myeloma; multiple sclerosis; myelogenous (e.g., AML and CML) and other leukemias; myopathies (e.g., muscle protein metabolism, esp. in sepsis); osteoporosis; Parkinson's disease; pain; pre-term labor; psoriasis; reperfusion injury; septic shock; side effects from radiation therapy, temporal mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma, orthopedic surgery, infection or other disease processes.
Inflammatory conditions of a joint are chronic joint diseases that afflict and disable, to varying degrees, millions of people worldwide. Rheumatoid arthritis is a disease of articular joints in which the cartilage and bone are slowly eroded away by a proliferative, invasive connective tissue called pannus, which is derived from the synovial membrane. The disease may involve peri-articular structures such as bursae, tendon sheaths and tendons as well as extra-articular tissues such as the subcutis, cardiovascular system, lungs, spleen, lymph nodes, skeletal muscles, nervous system (central and peripheral) and eyes (Silberberg (1985), Anderson's Pathology, Kissane (ed.), II:1828). Osteoarthritis is a common joint disease characterized by degenerative changes in articular cartilage and reactive proliferation of bone and cartilage around the joint. Osteoarthritis is a cell-mediated active process that may result from the inappropriate response of chondrocytes to catabolic and anabolic stimuli. Changes in some matrix molecules of articular cartilage reportedly occur in early osteoarthritis (Thonar et al. (1993), Rheumatic disease clinics of North America, Moskowitz (ed.), 19:635-657 and Shinmei et al. (1992), Arthritis Rheum., 35:1304-1308).
It is believed that rheumatoid arthritis results from the presentation of a relevant antigen to an immunogenetically susceptible host. The antigens that could potentially initiate an immune response that results in rheumatoid arthritis might be endogenous or exogenous. Possible endogenous antigens include collagen, mucopolysaccharides and rheumatoid factors. Exogenous antigens include mycoplasms, mycobacteria, spirochetes and viruses. By-products of the immune reaction inflame the synovium (i.e., prostaglandins and oxygen radicals) and trigger destructive joint changes (i.e., collagenase).
There is a wide spectrum of disease severity, but many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction and deformity. The clinical manifestations may include symmetrical polyarthritis of peripheral joints with pain, tenderness, swelling and loss of function of affected joints; morning stiffness; and loss of cartilage, erosion of bone matter and subluxation of joints after persistent inflammation. Extra-articular manifestations include rheumatoid nodules, rheumatoid vasculitis, pleuropulmonary inflammations, scleritis, sicca syndrome, Felty's syndrome (splenomegaly and neutropenia), osteoporosis and weight loss (Katz (1985), Am. J. Med., 79:24 and Krane and Simon (1986), Advances in Rheumatology, Synderman (ed.), 70(2):263-284). The clinical manifestations result in a high degree of morbidity resulting in disturbed daily life of the patient.
The involvement of interleukin-1 in arthritis has been implicated by two distinct lines of evidence. First, increased levels of interleukin-1, and of the mRNA encoding it, have been found in the synovial tissue and fluid of arthritic joints. See, for example, Buchan et al., "Third Annual General Meeting of the British Society for Rheumatology," London, England, Nov. 19-21, 1988, J. Rheumatol., 25(2); Fontana et al. (1982), Rheumatology Int., 2:49-53; and Duff et al. (1988), Monokines and Other Non-Lymphocytic Cytokines, M. Powanda et al. (eds), pp. 387-392 (Alan R. Liss, Inc.).
Second, the administration of interleukin-1 to healthy joint tissue has been shown on numerous occasions to result in the erosion of cartilage and bone. In one experiment, intra-articular injections of IL-1 into rabbits were shown to cause cartilage destruction in vivo (Pettipher et al. (1986), Proc. Nat'l Acad. Sci. U.S.A., 83:8749-8753). In other studies, IL-1 was shown to cause the degradation of both cartilage and bone in tissue explants (Saklatavala et al. (1987), Development of Diseases of Cartilage and Bone Matrix, Sen and Thornhill (eds.), pp. 291-298 (Alan R. Liss, Inc.) and Stashenko et al. (1987), The American Association of Immunologists, 183:1464-1468). One generally accepted theory which is used to explain the causal link between IL-1 and arthritis is that IL-1 stimulates various cell types, such as fibroblasts and chondrocytes, to produce and secrete proinflammatory or degradative compounds such as prostaglandin E.sub.2 and metalloproteinases.
Interleukin-1 receptor antagonist (IL-1ra) is a human protein that acts as a natural inhibitor of interleukin-1. IL-1 receptor antagonist (IL-1ra) has been disclosed as a potential agent for use in the clinical treatment of IL-1 mediated diseases (Australian Patent No. 649245). However, IL-1ra has a relatively short half-life. It therefore would be advantageous to administer IL-1ra in a sustained release formulation to treat IL-1 mediated diseases.
Hyaluronic acid is a naturally occurring mucopolysaccharide consisting of residues of D-glucoronic acid and N-acetyl-D-glucosamine in an unbranched chain. The polymer has an average molecular weight of (5-6).times.10.sup.6 and exhibits excellent biocompatibility. In the articular cartilage, hyaluronic acid plays an important role in the construction of the cartilage matrix by aggregating with proteoglycan. Furthermore, it has been reported that under pathological conditions such as rheumatoid arthritis, osteoarthritis and infectious arthritis, the concentrations and molecular weight of hyaluronic acid in the joint are changed and cause changes in the nature of the synovial fluid.
Both chemical cross-linking and derivatization have been used to enhance its rheological properties or increase the degradation time of certain drugs (Cortivo et al. (1991), Biomaterials, 2:727-730; Benedetti et al. (1990), J. Controlled Release, 13:33-41 and Hunt et al. (1990), J. Controlled Release, 12:159-169).
It has been shown that the injection of high molecular weight hyaluronic acid derivatives may restore the damaged hyaluronic acid layer on the articular cartilage surface and may be effective for treating some kinds of articular conditions in clinical and fundamental tests. Examples of scientific publications describing such use of hyaluronic acid derivatives for treatment of articular conditions include Nizolek & White (1981), Cornell Vet., 71:355-375; Namiki et al. (1982), Int. J. Chem. Pharmacol., Therapy and Toxicol., 20:501-507; Asheim and Lindblad (1976), Acta Vet Scand, 17(4):379-394; Svanstrom (1978), Proceedings of the 24th Annual Convention of the American Association of Equine Practitioners, St Louis, Mo., p. 345-348; Wigren et al. (1975), Upsala J Med Sci Suppl, 17:1-20; and Gingerich et al. (1980), Res Vet Sci, 30:192-197. An exemplary scientific publication describing the use of hyaluronic acid both alone and with cortisone in various animal joints, especially horses, is Rydell et al. (1971), Clinical Orthopaedics and Related Research, 80:25-32. The use of hyaluronic acid in human joints is reported by Peyron et al. (1974), Pathologie Biologie, 22(8):731-736. The intra-articular use of hyaluronic acid in horse joints has been commercially promoted in connection with Pharmacia's Hylartil.TM. and Hylartin V.TM. products and Sterivet's Synacid.TM. product. However, although symptoms such as pain and stiffness become a serious problem in the treatment of joint diseases, hyaluronic acid does not directly improve such symptoms.
Additionally, hyaluronic acid has been used for drug delivery. In one study, microspheres prepared from hyaluronic acid esters were used for the nasal delivery of insulin (Illum et al. (1994), J. Controlled Release, 29:133-141). Blank spheres were prepared by an emulsification/solvent evaporation technique, exposed to an insulin solution for an hour, and then lyophilized. When administered to sheep, the mean bioavailability was found to be 11% when compared with insulin administered by the subcutaneous route. This system has also been used as a delivery device for nerve growth factor (Ghezzo et al. (1992), Int. J. Pharm., 87:21-29). However, it has been reported that when certain hyaluronic acid compositions were admixed with the albumin, they enhanced the clearance rate of that protein from the synovial space (Myers and Brandt (1995), J. Rheumatol., 22:1732-1739), suggesting that a combination of hyaluronic acid with a protein, such as IL-1ra, would be no more effective than hyaluronic acid alone in the treatment of inflammatory diseases, particularly when administered via intrarticular injection.
It is an objective of the present invention to provide therapeutic methods and compositions for the treatment of IL-1 mediated inflammatory diseases. This and other objects of the present invention will become apparent from the description hereinafter.